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  • Title: Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells.
    Author: Osada S, Sakashita F, Hosono Y, Nonaka K, Tokuyama Y, Tanaka H, Sasaki Y, Tomita H, Komori S, Matsui S, Takahashi T.
    Journal: Cancer Chemother Pharmacol; 2008 Jul; 62(2):315-20. PubMed ID: 17922126.
    Abstract:
    BACKGROUND: Cytotoxicity of Vitamin K3 (VK3) is indicated to have the same mechanism with oxidative stress (H(2)O(2)). In the present study, we analyzed the differences and/or similarities in the cellular responses to oxidative stress and VK3 to clarify the mechanism of growth inhibition. METHODS: Cell viability was determined by a test method with 3-[4, 5-dimethyl-thiazol]-2, 5-dephenyl tetrazolium bromide (MTT). Expressions of cellular proteins were evaluated by Western blot analysis. RESULTS: The IC50 was calculated to be 47.3 +/- 4.1 microM for VK3 and 2.2 +/- 1.2 microM for H(2)O(2). By Western blot analysis, VK3 or H(2)O(2) was shown to induce rapid phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases (JNKs). H(2)O(2)-induced phosphorylation of ERK and JNK was almost complete inhibited by more than 100-muM genistein. VK3-induced JNK phosphorylation was blocked by 100-microM genistein, but ERK phosphorylation was not inhibited completely even if 400-microM genistein was used. H(2)O(2)-induced inhibition of cell proliferation was completely blocked by 400-microM genistein, but the VK3 effect was reduced 72.8 +/- 5.4% by the same concentration of genistein. H(2)O(2)-induced JNK phosphorylation and ERK phosphorylation were inhibited by staurosporine, protein kinase C (PKC) inhibitor. VK3-induced JNK phosphorylation was also blocked, but ERK phosphorylation was not affected. Staurosporine had no effect on VK3- or H(2)O(2)-induced growth inhibition. Treatment with a non-thiol antioxidant agent, catalase, completely abrogated H(2)O(2)-induced JNK and ERK phosphorylation, but a thiol antioxidant, L: -cystein, had no effect on phosphorylation of them. The VK3-induced JNK phosphorylation was inhibited by catalase, but not L: -cystein. But ERK phosphorylation was not inhibited by catalase and was abrogated completely by the thiol antioxidant. Catalase, but not L: -cystein, blocked H(2)O(2)-induced growth inhibition, and L: -cystein, but not catalase, blocked VK3-induced effects on cell proliferation completely. CONCLUSION: VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.
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